In the field of nuclear medicine, functional imaging of the human brain has yielded insight in to the early stages of various human dementias, including Alzheimer's Disease. Using well known techniques such as Positron Emission Tomography (PET) scanning and Single Photon Emission Computed Tomography (SPECT) imaging, researchers have, for instance, found specific patterns of brain activity, or signatures, characteristic of particular dementia. Early stage Alzheimer's Disease is characterized by a decrease in resting state, or basal, metabolic activity within certain regions of the cerebral cortex, which are diagnostic of Alzheimer's with an accuracy of 85% or better. Even greater accuracy is obtained using the knowledge that in early Alzheimer's, the same regions of compromised metabolic activity maintain their ability to increase blood flow, or perfusion, in response to stimulants. This Alzheimer's signature pattern of a positive effect of stimulants on cerebral perfusion but a compromised basal metabolism is particularly evident in areas such as the hippocampus (mesial temporal) and the parieto-occipital cortex.
In contrast, vascular dementia, which in theory may affect any vascular territory of the brain, often also affects the parieto-occipital cortex, which is essentially in a watershed territory between the major cerebral arteries contributing to the anterior and posterior cerebral circulation. The signature pattern of vascular dementia is opposite to Alzheimer's (or most other neurodegenerative disorders), in that cerebrovascular flow reserve, or the ability to demonstrate a positive response to a cerebral perfusion stimulant, is not only absent but typically compromised in cerebrovascular disease, which is most often responsible for vascular dementia. These signature patterns are potentially a very effective way to screen patients to detect the onset of Alzheimer's or vascular dementia at an early stage so that appropriate treatment may be administered before the disease process is more advanced and most therapies are less likely to be effective.
PET and SPECT scanning, which provide three dimensional information about brain metabolism and perfusion and can thus even distinguish the not infrequent patients with mixed patterns (eg. patients with a component of cerebrovascular disease predominating in one area and a component of Alzheimer's disease predominating in another area), are; however, time consuming and require very costly equipment and support infrastructure.
In PET scanning, the patient is given a short-lived radioactive tracer isotope that decays by emitting a positron. The radioactive isotope is chemically incorporated into a metabolically active molecule that is typically injected into the patient's blood circulation. After waiting typically about an hour for the molecule to become concentrated in the tissues of interest, the patient is placed in the imaging scanner. A commonly used molecule for brain scanning is F18 (half-life 109 minutes) labeled 2-fluoro-2-Deoxyglucose (FDG), a sugar that can cross the blood-brain barrier. The positron particle derived from FDG in actually an anti-matter particle, that almost immediately collides with an electron (typically the most available normal matter). The resulting annihilation reaction yields two 511 keV gamma photons that are emitted in very nearly opposite directions. Using coincidence detectors with pico-second temporal resolution and sophisticated computers, the position of the original decay can be calculated to within a fraction of a millimeter. This also requires a correction for attenuation of the 511 keV gamma rays within the brain, skull and other tissues of the head, which is typically derived from a second set of measurements with another radioactive source, including more recently, an x-ray computerized tomographic (CT) scanner, which may be coupled into a single expensive (on the order of two million dollars) PET-CT instrument. The result is a three dimensional image of the activity in the brain (or other body part), whose resolution remarkably depends mainly on the few millimeters the original positron may have traveled before it encountered an electron.
SPECT imaging is a little less complex, using a gamma camera to acquire multiple two-dimensional images, or projections, from multiple angles. A computer is then used to apply a tomographic reconstruction algorithm to the multiple projections, yielding a three dimensional dataset. As with PET, attenuation of the emitted gamma ray may be corrected with a significant increased cost by combining another gamma ray source to produce another image of the density (with respect to gamma rays) of the scanned object, or a combined SPECT-x-ray CT scanner. Most SPECT cameras in routine use do not correct directly for attenuation, but may use a calculated attenuation correction, which is typically less accurate. The radioactive isotope typically used in SPECT imaging is technetium 99 (Tc-99), which decays by gamma emission, emitting 140 keV gamma rays. Tc-99 has a half-life of 6.02 hours, considerably longer than the 109 min half life of the F18 FDG used in PET scanning. Moreover, it can be made in a relatively simple process from a source of decaying molybdenum-99 (Mo-99). Mo-99 has a half-life of 66 hours and can be easily transported over long distances to hospitals, while FDG is made in an expensive medical cyclotron and delivered directly to the scanning site. While the widespread delivery of F18 is challenging, the growth of PET imaging for oncology and other uses has made it reasonably available throughout most of the United States and most other industrialized nations. Other PET tracers, such as those used for PET perfusion measurements have much shorter half-lives (eg. oxygen-15 labelled water with half-life about two minutes) and are only available in major medical or scientific centers.
Perhaps more important than the issue of attenuation corrections, which are imperfect but not so very important for measurements pertaining to a tissue such as the cortex of the brain, which is quite superficial (attenuation corrections are more critical for deeper structures) are related issues pertaining to background and scattered radiation. In this context background applies not only to minimal activity from natural sources such as cosmic rays, but also considerable activity from the various tissues in the head apart from the neuronal cells. Thus, activity from blood vessels, the pituitary gland, the skin and subcutaneous tissues, facial muscles and ependymal cells in the choroid plexus all contribute background activity which must be resolved from nearby neuronal activity. Most of these sources of background activity are outside the blood-brain barrier. Clearly, PET and SPECT tracers of cerebral perfusion and metabolism cross the blood brain barrier, but they are also present in the tissues outside the blood brain barrier. In fact, when first injected, the PET or SPECT tracers are entirely within the bloodstream. Depending on the patient's overall metabolism, a variable time (typically about an hour) passes before blood levels decrease to such an extent that they contribute only a small background to the brain image based mainly on perfusion and/or metabolism of the neuronal cells that is actually responsible for the recognizable patterns of activity in specific forms of dementia. Scattered radiation, related to incomplete absorption of gamma rays, specifically Compton scattering, is a principal factor degrading resolution of nuclear medicine images, even PET images that in part correct for this effect by the coincidence counting described above. While these sources of background are not such a problem as to negate the excellent results of PET and SPECT images which may correct for them to variable degrees, especially in research applications, practical ways to deal with them in everyday clinical applications would be a significant advance.
What is needed to make more practical use of the insights into brain function yielded by PET and SPECT imaging is a simple, low cost gamma radiation monitoring instrument capable of reliable measure of basal and stimulated activity within the cerebral cortex and other parts of the brain, using small and potentially inexpensive quantities of easily transported radioisotopes. Such an instrument, when applied with the appropriate methodology, may for instance, use the signature patterns discovered using PET and SPECT imaging as an effective way to screen populations to detect the onset of dementia. It would also be important if such an instrument would further enable increased accuracy without undue increased cost or inconvenience by simple approximations to background corrections which otherwise contribute to error in determining diagnostic patterns of neuronal activity.
This latter consideration becomes even more important in screening application where use of an oral tablet of FDG (known to have a very similar eventual bio-distribution as an injected dose of FDG) could be used to avoid the inconvenience of an injection, but at the expense of a longer and more variable time for absorption into, and subsequent clearance of the tracer from, the bloodstream. Moreover, an instrument allowing simultaneous measure of cerebral perfusion and metabolism, through the use of separate tracers in small amounts, would have significant advantages in recognition of cerebral patterns of activity as compared to PET, all of whose tracers produce the same 511 keV gamma rays and can therefore only be practicably measured sequentially, rather than simultaneously, or even SPECT, whose sensitivity and relatively low energy resolution are typically insufficient to permit widespread use of simultaneous dual tracer studies because of the risks of an increased radiation dose.